1. Field of the Invention
The present invention is directed to novel 4-ethyl and 4-ethenyl-5-hydroxy-2(5H)-furanones substituted on the alpha carbon of the ethyl or ethenyl side chain with a long chain alkyl group and on the beta carbon with a polar group, which compounds are active as anti-inflammatory agents. The present invention is also directed to pharmaceutical compositions which comprise one or more of the novel compounds of the invention, to the methods of using these pharmaceutical compositions, and to the chemical processes of making the novel compounds.
2. Brief Description of the Prior Art Manoalide is a compound isolated from a marine sponge [E. D. de Silva et al., Tetrahedron Letters 21:1611-1614 (1980)] which has anti-inflammatory, immunosuppressive and analgesic properties. Manoalide (Compound 1) the structure of which is shown below, includes a 5-hydroxy-2(5H)-furanone moiety, attached in the 4-position of the furanone ring to the rest of the molecule. Certain analogs of manolide, such as seco-manoalide (Compound 2) and dehydro-seco-manoalide (Compound 3) also have anti-inflammatory inflammatory activity. For further description of the biological activity of manoalide and some of its derivatives reference is made to U.S. Pat. No. 4,447,445 and to European Patent Application No. 0133376 (published on Feb. 20, 1985). ##STR2##
Synthetic analogs of manoalide, particularly analogs having various substituents on the furanone moiety of manoalide, are described in several applications for United States Letters Patent by the same inventor as in the present application, the following of which have been allowed and are expected to issue as United States Letters Patent:
Ser. No. 259,225 filed on Oct. 18, 1988; PA0 Ser. No. 281,126 filed on Dec. 7, 1988. PA0 Formula 24, Compound 8: W.dbd.H, X.dbd.CH.sub.3 --(CH.sub.2).sub.11 and Y.dbd.COCH.sub.3 ; PA0 Formula 24, Compound 9: W.dbd.H, X.dbd.CH.sub.3 --(CH.sub.2).sub.11 and Y.dbd.COCF.sub.3 ; PA0 Formula 24, Compound 10: W.dbd.H, X.dbd.CH.sub.3 --(CH.sub.2).sub.11 and Y.dbd.C(CH.sub.3).sub.2 OH; PA0 Formula 24, Compound 11: W.dbd..dbd.CO.sub.2 CH.sub.3, X.dbd.CH.sub.3 --(CH.sub.2).sub.11 and Y.dbd.CO.sub.2 CH.sub.3 ; PA0 Formula 24, Compound 12: W.dbd.H, X.dbd.CH.sub.3 --(CH.sub.2).sub.11 and Y.dbd.COOH; PA0 Formula 24, Compound 13: W.dbd.H, X.dbd.CH.sub.3 --(CH.sub.2).sub.11 and Y.dbd.PO(OCH.sub.2 CH.sub.3).sub.2 ; PA0 Formula 24, Compound 14: W.dbd.H, X.dbd.5-(2,4,5-trifluorophenyl)pentyl and Y.dbd.COCF.sub.3 ; PA0 Formula 24, Compound 15: W.dbd.H, X.dbd.CH.sub.3 --(CH.sub.2).sub.11 and Y.dbd.CH.dbd.NOCH.sub.3 ; PA0 Formula 24, Compound 16: W.dbd.H, X.dbd.CH.sub.3 --(CH.sub.2).sub.11 and Y.dbd.CONH.sub.2 ; PA0 Formula 24, Compound 17: W.dbd.H, X.dbd.CH.sub.3 --(CH.sub.2).sub.11 and Y.dbd.CH.dbd.NOH; PA0 Formula 24, Compound 18; W.dbd.H, X.dbd.CH.sub.3 --(CH.sub.2).sub.11 and Y.dbd.CH.dbd.NNHCH.sub.3 ; PA0 Formula 24, Compound 19; W.dbd.H, X.dbd.CH.sub.3 --(CH.sub.2).sub.11 and Y.dbd.COCF.sub.2 H; PA0 Formula 24, Compound 20: W.dbd.H, X.dbd.CH.sub.3 --(CH.sub.2).sub.11 and Y.dbd.PS(OCH.sub.2 CH.sub.3).sub.2 ; PA0 Formula 24, Compound 21: W.dbd.H, X.dbd.CH.sub.3 --(CH.sub.2).sub.11 and Y.dbd.SO.sub.2 CH.sub.3 ; PA0 Formula 24, Compound 22: W.dbd.H, X.dbd.CH.sub.3 --(CH.sub.2).sub.11 and Y.dbd.CCH.sub.3 .dbd.NOH; PA0 Formula 25, Compound 23: X.dbd.CH.sub.3 --(CH.sub.2).sub.11 and Y.dbd.COCF.sub.3, and PA0 Formula 25, Compound 24: X.dbd.CH.sub.3 --(CH.sub.2).sub.11 and Y.dbd.PO(OCH.sub.2 CH.sub.3).sub.2 ; PA0 a. Bee venom phospholipase A.sub.2 in 10 uM HEPES (pH 7.4) with 1 mM CaCl.sub.2 is incubated with vehicle or test agent for 1.0 hour at 41.degree.. PA0 b. 1.36 mM phosphotidylcholine, 2.76 mM Triton X-100 are dispersed in buffer by sonication and then mixed with L-3 phosphotidylcholine, 1-palmitoyl-2-(1-.sup.14 C) palmitoyl for 10 min. PA0 c. Start the reaction by the addition of enzyme (0.495 units/ml). PA0 d. Incubation for 15 sec. at 41.degree.. PA0 e. Reaction is terminated by addition of 2.5 ml of isopropanol: n-heptane: 0.5 M H.sub.2 SO.sub.4 (40:10:1; v:v:v:). PA0 f. 2.0 ml n-heptane and 1.0 ml H.sub.2 O added; mixture centrifuged. PA0 g. 2.0 n-heptane removed and treated with 200-300 mg of silica gel HR60. PA0 h. Samples centrifuged; 1 ml of n-heptane SN removed and added to 10 ml scintillation fluid. PA0 i. Samples counted on a scintillation counter.
Published European Patent Application No. 0 295 056 discloses 4-substituted 5-hydroxy-2(5H)-furanones having anti-inflammatory, immunosuppressive and anti-proliferative activity where the substituents in the 4 position are a variety 1-hydroxyalkyl, 1-acyloxy-alkyl and 1-carbamoyloxy-alkyl groups.